Leishmaniasis is a widespread and debilitating protozoal disease of man and animals. An improved understanding of the immunologic aspects of this infection should provide the basis for new-therapies. We propose to study aspects of chronic leishmaniasis in a murine model of human leishmaniasis. Experimental infections in mice mimic to a large extent the spectrum of clinical presentations associated with human disease, and have been used extensively to study immunologic responses in leishmaniasis. From such studies we have learned a great deal about the factors involved in the differentiation and regulation of T cell subsets. In contrast, however, we know much less about the events involved in the resolution of leishmanial lesions. In this proposal we will define the mechanisms involved in the resolution of lesions associated with Leishmania infection. We will concentrate on the three critical events involved in lesion resolution, namely, macrophage activation to clear the parasites, regulation of the adhesion molecules that control infiltration of cells into lesions, and death or apoptosis of the cells within the lesion site. Since tumor necrosis factor (TNF) contributes to each of these events, we will in large part focus on TNF and the two receptors, TNF receptor p55 and p75, that mediate the functions of TNF. Mice lacking these receptors have been produced, and we find that TNF receptor deficient mice are able to control and eliminate their parasites, but fail to resolve their lesions. The infection in these mice is similar to certain chronic forms of human leishmaniasis, and will provide a model to study lesion resolution. Using these animals we will be able to define the critical events in lesion resolution. Our aims will be to: (l) further characterize L. major infection in TNF receptor deficient mice; (2) define the role that apoptosis of cells plays in the resolution of lesions; and (3) define the TNF independent pathway of macrophage activation operating in the TNF receptor deficient mice. We anticipate that the information gained from these studies will be useful in understanding non-healing forms of human leishmaniasis associated with a sustained inflammatory response, and more broadly, will provide information relevant for treating other forms of chronic disease.